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Co As a Cellular Signaling Molecule 26 Dec 2005 17:21 AR AR267-PA46-15.tex XMLPublishSM(2004/02/24) P1: JRX 10.1146/annurev.pharmtox.46.120604.141053 Annu. Rev. Pharmacol. Toxicol. 2006. 46:411–49 doi: 10.1146/annurev.pharmtox.46.120604.141053 Copyright c 2006 by Annual Reviews. All rights reserved First published online as a Review in Advance on September 30, 2005 CO AS A CELLULAR SIGNALING MOLECULE Hong Pyo Kim, Stefan W. Ryter, and Augustine M.K. Choi Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213; email: [email protected], [email protected], [email protected] KeyWords carbon monoxide, guanylate cyclase, mitogen-activated protein kinase, stress response ■ Abstract Many biological functions of heme oxygenase (HO), such as cytopro- tection against oxidative stress, vasodilation, neurotransmission in the central or pe- ripheral nervous systems, and anti-inflammatory, anti-apoptotic, or anti-proliferative potential, have been attributed to its enzymatic byproduct carbon monoxide (CO), al- though roles for biliverdin/bilirubin and iron have also been proposed. In addition to these well-characterized effects, recent findings reveal that HO-derived CO may act as an oxygen sensor and circadian modulator of heme biosynthesis. In lymphocytes, CO may participate in regulatory T cell function. A number of the known signaling effects of CO depend on stimulation of soluble guanylate cyclase and/or activation of mitogen-activated protein kinases (MAPK). Furthermore, modulation of caveolin-1 status may serve as an essential component of certain aspects of CO action, such as growth control. In this review, we summarize recent findings of the beneficial or detri- mental effects of endogenous CO with an emphasis on the signaling pathways and downstream targets that trigger the action of this gas. INTRODUCTION Living organisms have developed highly conserved enzymatic systems that gener- ate small gaseous molecules, such as nitric oxide (NO),∗ carbon monoxide (CO), and hydrogen sulfide (H2S) (1–4). Coinciding with the development of industry, Annu. Rev. Pharmacol. Toxicol. 2006.46:411-449. Downloaded from www.annualreviews.org Access provided by 2402:3a80:a95:ab2d:b0b2:ce30:6d69:7579 on 04/11/20. For personal use only. ∗Abbreviations: bHLH: basic helix loop helix; cGMP: guanosine 3,5-monophosphate; CNS: central nervous system; CO: carbon monoxide; EC: endothelial cells; HBP1: high mo- bility group-box protein-1; HO: heme oxygenase: HO-1: heme oxygenase-1; HO-2: heme oxygenase-2; Hsp70: 70-kDa heat shock protein; I/R: ischemia/reperfusion; LDL: low- density lipoprotein; MAPK: mitogen activated protein kinase; NO: nitric oxide; NPAS-2: neuronal PAS domain protein-2; p38 MAPK: p38 mitogen activated protein kinase; PDGF: platelet-derived growth factor; PKG: protein kinase G; pRB: retinoblastoma protein; sGC: soluble guanylate cyclase; SnPP-IX: tin-protoporphyrin IX; SMC: (vascular) smooth mus- cle cells; TGF-β1: transforming growth factor-β1; TNF-α: tumor necrosis factor-alpha; UVA: ultraviolet-A; ZnPP-IX: zinc protoporphyrin-IX. 0362-1642/06/0210-0411$20.00 411 26 Dec 2005 17:21 AR AR267-PA46-15.tex XMLPublishSM(2004/02/24) P1: JRX 412 KIM RYTER CHOI Figure 1 Catabolism of heme by heme oxygenase (HO). Equimolar CO, iron, and biliverdin are produced by HO enzymatic activity. Biliverdin is further metabolized by biliverdin reductase to bilirubin (A). A major source of endogenous CO arises from the degradation of erythrocytes and hemoproteins (B). these molecules are also widely known as toxic air pollutants. Regardless of their notoriety, recent findings reveal that trace amounts of these gaseous molecules are indispensable for maintaining the biological system and defending the host from hostile environments (5). Physiological NO, as implicated in vasoregulation and immune function, arises from the conversion of L-arginine to L-citrulline by con- stitutive and inducible nitric oxide synthase (NOS) enzymes. On the other hand, endogenous CO evolves primarily from the enzymatic degradation of heme by the heme oxygenase enzyme system (HO; E.C. 1:14:99:3) (6–8) (Figure 1A and B). HO provides the first and rate-limiting step in the oxidation of heme, leading to the formation of biliverdin-IXα, with the concomitant liberation of CO and Annu. Rev. Pharmacol. Toxicol. 2006.46:411-449. Downloaded from www.annualreviews.org Access provided by 2402:3a80:a95:ab2d:b0b2:ce30:6d69:7579 on 04/11/20. For personal use only. reduced heme iron. Heme metabolism concludes with the enzymatic reduction of billiverdin-IXα by NAD(P)H:biliverdin reductase (6, 9). At least two distinct isoforms of HO exist, a constitutive form (HO-2) and an inducible form (HO-1) responsive to transcriptional activation by a broad array of chemical and physical stress (8, 10). Over the past decade, HO-1 has attracted intensive interest as a mediator of tis- sue protection and host defense. Efforts to dissect the underlying mechanisms of cell and tissue protection have revealed possible contributory mechanisms based on the evolution of all the major HO end-products, including CO (reviewed in 11). Because this represents primarily a review on the role of CO in intracellular 26 Dec 2005 17:21 AR AR267-PA46-15.tex XMLPublishSM(2004/02/24) P1: JRX CO AND CELLULAR SIGNALING 413 signaling, we refer the reader to other recent reviews for discussion of the possi- ble roles of biliverdin/bilirubin and iron metabolism in HO-mediated protection (11–13). HO-derived CO was formerly considered as a catabolic elimination product with no physiological significance (14). Indeed, elevated CO concentrations cause tissue hypoxia by virtue of competitive binding with the oxygen binding sites of hemoglobin (15, 16). A signaling role for CO first emerged from observations that CO can weakly stimulate soluble guanylate cyclase (sGC) in vitro by heme bind- ing to produce guanosine 3,5-monophosphate (cGMP), as well as stimulate the production of cGMP when directly applied to vascular smooth muscle cells (SMC) (17–19). HO-derived CO and downstream effects on cGMP formation have been implicated in a number of neuronal signaling processes, including olfactory neu- rotransmission (5, 20, 21–24). Furthermore, CO has been implicated in vascular processes such as regulation of vessel tone (25–30), SMC proliferation (31–34), and platelet aggregation (34–36). An exclusive or unequivocal role for sGC in all signaling processes triggered by CO has not been established, leaving the ques- tion open for the resolution of other possible molecular targets. Indeed, CO has been shown to modulate the activation state of mitogen-activated protein kinases (MAPK) critical for cellular signal transduction in response to stress and inflamma- tion. CO exerts novel anti-inflammatory, anti-apoptotic, and anti-proliferative ef- fects dependent on the modulation of the p38 MAPK signaling pathway (Figure 2). Over the past decade, CO applied at low concentration has been shown to confer cyto- and tissue-protective effects akin to HO-1 elevation in numerous models of tissue injury and disease, including oxidative lung injury, inflammation, and organ transplantation (37–39, reviewed in 40). Recent observations from this laboratory Annu. Rev. Pharmacol. Toxicol. 2006.46:411-449. Downloaded from www.annualreviews.org Access provided by 2402:3a80:a95:ab2d:b0b2:ce30:6d69:7579 on 04/11/20. For personal use only. Figure 2 c-GMP-dependent or -independent CO signaling. 26 Dec 2005 17:21 AR AR267-PA46-15.tex XMLPublishSM(2004/02/24) P1: JRX 414 KIM RYTER CHOI reveal additional candidate molecules that function as downstream targets of CO signaling, including the 70-kDa heat shock protein (Hsp-70) and caveolin-1 (31, 41). This review describes the major signaling pathways by which CO exerts potent and diverse actions on cellular homeostasis. TRANSCRIPTIONAL REGULATION OF HO-1 HO-1 is transcriptionally upregulated as a sensitive cytoprotective protein by var- ious types of oxidative stress, such as oxidized low-density lipoprotein (LDL), ultraviolet-A (UVA) radiation, thiol-reactive substances and by growth factors, hormones, disease states, and dietary antioxidants including various classes of natural products. There is no commonality among HO-1 inducers, which have di- verse chemical structures ranging from proteins to small organic compounds to a gas molecule (NO) (reviewed in 42). HO-1 is widely accepted as a cellular defense mechanism against harmful or noxious stimuli, such as sodium arsenite or metal ions (43, 44, reviewed in 45). Although clearly depictive, we further categorize the HO-1 induction depending on the modes of action mechanism. Synergistic Induction If the induction and function of HO-1 parallels with the physiological activity of a given stimulus, it may be grouped in the category of a synergistic response. In such examples, the presence of HO-1 is required for the therapeutic effect of the primary stimuli, which is mediated presumably by the reaction products of HO activity. In this way, HO-1 can amplify the therapeutic effects of certain stimuli, such as the anti-inflammatory cytokine IL-10 (46), the anti-proliferative rapamycin (47), 15-PGJ2 (48), and aspirin/salicylic acid (49). For instance, IL-10 stimulates the upregulation of HO-1, and subsequently a product(s) of the degrada- tion of heme by HO-1 mediates the therapeutic effect of IL-10. Accumulating data with clinical therapeutics and Oriental medicines also support that HO activity may amplify therapeutic potential. Cholesterol-independent, pleiotropic actions of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert anti-inflammatory and antioxidant action (50). Grosser et al. show that HO-1 is a target site of statins in endothelial cells. In cultured human umbilical vein Annu. Rev. Pharmacol. Toxicol. 2006.46:411-449. Downloaded from www.annualreviews.org Access provided by 2402:3a80:a95:ab2d:b0b2:ce30:6d69:7579 on 04/11/20. For personal use only. endothelial cells, simvastatin and lovastatin increase HO-1 mRNA levels in a concentration- and time-dependent, but NO-independent fashion.
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